Biphasic induction of immediate early gene expression accompanies activity-dependent angiogenesis and myofiber remodeling of rabbit skeletal muscle.

Sustained contractile activity of skeletal muscle promotes angiogenesis, as well as transformation of contractile protein isoforms and mitochondrial proliferation within myofibers. Since the products of immediate early genes such as c-fos, c-jun, and egr-1 function in many signaling pathways governing cellular responses to external stimuli, we sought to determine whether sustained contractile activity induces their expression in skeletal muscle. Low voltage electrical stimulation was applied to the motor nerve innervating rabbit tibialis anterior muscles for periods ranging from 45 min to 21 d. Northern and Western analysis demonstrated marked but transient inductions of c-fos, c-jun, and egr-1 mRNA and protein within the first 24 h. Longer durations of stimulation were associated with a secondary and sustained rise in the abundance of c-fos, c-jun, and p88egr-1 protein that, surprisingly, was not accompanied by detectable changes in mRNA. Immunohistochemistry demonstrated c-fos immunoreactivity within myofiber and vascular cell nuclei during both early and late phases of this response. These findings reveal a complex pattern of c-fos, c-jun, and egr-1 expression in response to nerve stimulation and suggest that these proteins could function in regulatory pathways that modify muscle phenotype.

Effects of long-term cigarette smoking on the human locus coeruleus.

BACKGROUND: It has been hypothesized that cigarette smoking among subjects with major depression is a form of self-medication. To explore a possible biological basis for this hypothesis, noradrenergic proteins in the locus coeruleus (LC) were measured in long-term cigarette smokers and in nonsmokers. The LC was studied because elevated amounts of alpha2-adrenoceptors and tyrosine hydroxylase have been observed postmortem in the LCs of subjects with major depression or who commit suicide, and because long-term administration of antidepressant drugs to rats down-regulates these proteins in the LC. METHODS: Postmortem LCs were obtained from long-term cigarette smokers (n=7) and from nonsmokers (n = 9), all of whom lacked diagnoses of major depression. Amounts of tyrosine hydroxylase immunoreactivity and radioligand binding to the norepinephrine transporter, monoamine oxidase A, and alpha2-adrenoceptors were measured. RESULTS: Amounts of tyrosine hydroxylase immunoreactivity and radioligand binding to alpha2-adrenoceptors were significantly lower (approximately 60% and 40%, respectively) along the axis of the LCs of long-term smokers compared with nonsmokers. Smoking had no statistically significant effects on binding to monoamine oxidase A or to the norepinephrine transporter. CONCLUSION: This is the first demonstration that cigarette smoking affects noradrenergic proteins in the LC. The direction of these changes is opposite to that observed when comparing subjects who have major depression with normal controls and the same as that produced by long-term antidepressant treatment in animals. If the present observations reflect long-term effects of smoking on premortem noradrenergic biochemistry, smoking-induced changes in LC biochemistry may strengthen the smoking habit among subjects with major depression.

Role of prostaglandins in initiating cardiovascular reflexes originating from the pancreas and the gall bladder.

The application of bradykinin or other algesic substances to the serosal surface of the gall bladder or the pancreas evokes reflex increases in cardiovascular function. The purpose of the present study was to determine whether prostaglandins modulate these reflex responses when visceral receptors are activated by bradykinin. The application of bradykinin or capsaicin to the gall bladder and the pancreas initially elicited increases in arterial pressure in anaesthetised cats. Local inhibition of prostaglandin synthesis with indomethacin greatly attenuated the pressor response to activation of gall bladder or pancreatic receptors by bradykinin. The pressor response to capsaicin was not altered by indomethacin. Thus prostaglandins appear to be involved in the activation of visceral receptors by bradykinin, which results in an increase in cardiovascular function.

Effects of static and rhythmic twitch contractions on the discharge of group III and IV muscle afferents.

Although both static and rhythmic twitch contractions of the hindlimb muscles of anaesthetised cats have been shown to reflexly evoke pressor responses, the increase in arterial pressure evoked by the former type of contraction has been shown to be substantially larger than that evoked by the latter. We have therefore recorded the impulse activity of single group III and IV muscle afferents, whose activation reflexly increases arterial pressure, while we both statically and rhythmically twitch-contracted the triceps surae muscles of anaesthetised cats. We found that group III afferents (n = 17) discharged significantly more impulses in response to static contraction than in response to rhythmic contraction. By contrast, group IV afferents (n = 18) fired approximately the same number of impulses in response to the two types of contraction. In addition, we found that many of the group III but only a few of the group IV afferents displayed discharge properties suggestive that these afferents were mechanoreceptors. We conclude that the discharge of group III afferents are likely to be responsible for the difference in the magnitudes of the reflex pressor responses evoked by static and rhythmic contraction.

Beta adrenergic blockade with propranolol and atenolol in the exercising dog: evidence for beta 2 adrenoceptors in the sinoatrial node.

To test the hypothesis that beta 2 adrenergic receptors mediate the chronotropic more than the inotropic response to endogenous catecholamines the effects on the haemodynamic responses to exercise in dogs of the beta 1 specific antagonist atenolol were compared with those of the non-selective beta antagonist propranolol. Heart rate, left ventricular dP/dt at 40 mmHg developed pressure (dP/dt40), and oxygen consumption (VO2) were determined at seven to eight exercise levels in 16 chronically instrumented adult mongrel dogs with and without beta blockade. In doses that produced equivalent suppression of resting heart rate, propranolol and atenolol affected dP/dt40 similarly at all exercise levels. In contrast to atenolol, which affected heart rate equally at all workloads, propranolol inhibited heart rate more as the workload increased, resulting in a 1.55-fold greater percentage inhibition of chronotropy at a VO2 of 60 ml.Kg-1.min-1 a than at a VO2 of 30 ml.kg-1.min-1. These results are compatible with the hypothesis that, although beta 2 receptors appear to have little influence over cardiac inotropy during exercise, sinoatrial beta 2 receptors may be stimulated by circulating catecholamines and contribute greatly to sympathetic modulation of heart rate during heavy exercise in dogs.

Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression.

BACKGROUND: Levels of tyrosine hydroxylase (TH) are regulated in the noradrenergic locus coeruleus (LC) in response to changes in the activity of LC neurons and in response to changes in brain levels of norepinephrine. To study the potential role of central noradrenergic neurons in the pathobiology of major depression, TH protein was measured in the LC from postmortem brains of 13 subjects with a diagnosis of major depression and 13 age-matched control subjects having no Axis I psychiatric diagnosis. Most of the major depressive subjects died as a result of suicide. METHODS: Protein from sections cut through multiple rostro-caudal levels of LC was transferred to Immobilon-P membrane, immunoblotted for TH, and quantified autoradiographically. RESULTS: The distribution of TH-immunoreactivity (TH-ir) along the rostro-caudal axis of the LC was uneven and was paralleled by a similar uneven distribution of neuromelanin-containing cells in both major depressive and psychiatrically normal control subjects. Amounts of TH-ir in the rostral, middle and caudal levels of the LC from major depressive subjects were significantly higher than that of matched control subjects. There were no significant differences in the number of noradrenergic cells at any particular level of the LC comparing major depressive subjects to control subjects. CONCLUSIONS: Elevated expression of TH in the LC in major depression implies a premortem overactivity of these neurons, or a deficiency of the cognate transmitter, norepinephrine.

Autoradiographic comparison of [3H]-clonidine binding to non-adrenergic sites and alpha(2)-adrenergic receptors in human brain.

UNLABELLED: Clonidine is a partial agonist at brain alpha(2)-adrenoceptors (alpha(2)AR), but also has high affinity (K(D) = 51 nM) in homogenate binding assays for non-adrenergic imidazoline-binding sites (I-sites; imidazoline receptors). Herein, an autoradiographic comparison of [3H]-clonidine binding to I-sites and alpha(2)AR in sections of human brain is reported. For I-sites, the adrenergic component of 50 nM [3H]-clonidine binding was masked with either 60 microM norepinephrine (NE; alpha(2)AR agonist) or 12.5 microM methoxy-idazoxan (MIDX; selective alpha(2)AR antagonist), whereas the remaining non-adrenergic sites were studied by displacement with 20 microM cirazoline. Levels of [3H]-clonidine binding to alpha(2)AR and I-sites, determined in adjacent tissue sections, were positively correlated across 27 brain regions (p = 0.0003; r(2) = 0.385). The principal olivary nucleus and the rostral portion of the ventrolateral medulla had highest ratios of I-sites: alpha(2)AR (>4:1). Quantitative transepts drawn across hippocampal images revealed alpha(2)AR enrichments in the CA-1 and inner molecular layers of the dentate gyrus-areas not enriched in I-sites. Competition curves were generated for I-sites in caudate sections using 10 ligands known to distinguish between I(1) and I(2) subtypes. The rank-order of affinities were cirazoline > harmane > BDF6143 > idazoxan = tizanidine (affinities of agmatine, efaroxan, moxonidine, NE, and oxymetazoline were too low to be reliable). Only the endogenous I-site ligand, harmane, had a monophasic displacement curve at the non-adrenergic sites (Ki = 521 +/- 12 nM). IN CONCLUSION: 1) the distribution of non-adrenergic [3H]-clonidine binding sites in human brain sections was correlated with, but distinct from alpha(2)AR; and 2) the affinities of these sites was distinct from alpha(1)AR, alpha(2)AR, I(1) or I(2) sites as previously defined in membrane binding assays. The properties of this non-adrenergic [3H]-clonidine binding site are consistent with I-sites previously labeled by [3H]-cirazoline in rat brain.

Brain noradrenergic receptors in major depression and schizophrenia.

The binding of [125I]p-iodoclonidine to alpha-2, and/or [125I]iodopindolol to beta-1 and beta-2 adrenoceptors was measured in right prefrontal cortex (Brodmann's area 10) and right hippocampus from subjects with DSM-III-R diagnoses of major depression (n = 15) or schizophrenia (n = 8) as well as from control subjects (n = 20). No significant differences between study groups were observed in binding to alpha-2 adrenoceptors in any of the six layers of prefrontal cortex or in any of the hippocampal fields. Likewise, there were no significant differences in beta-1 or beta-2 adrenoceptor binding in any of the hippocampal fields between control and major depressive subjects. In contrast, binding to beta-1 adrenoceptors, but not beta-2 adrenoceptors, was significantly lower (-13 to -27%) in most hippocampal fields of schizophrenic subjects as compared to control subjects or to major depressives. Alterations in beta-1 adrenoceptor binding in the hippocampus of schizophrenics provide further evidence for a role of central noradrenergic neurons in the neurochemical pathology of schizophrenia.

Effects of prenalterol on beta adrenergic responsiveness and receptors in the cerebral cortex of the rat.

The activity of the beta-adrenoceptor agonist, prenalterol, at beta adrenoceptors in the cerebral cortex of the rat and the effect of chronic intraperitoneal infusion of prenalterol on the biochemical responsiveness and density of cerebral cortical beta adrenoceptors was studied. Whereas isoproterenol caused a four-fold rise in the content of cyclic AMP in slices of cerebral cortex, prenalterol did not produce a significant increase in cyclic AMP. However, prenalterol inhibited the isoproterenol-stimulated increase in cyclic AMP in cortical slices in a concentration-dependent manner. Using an in vivo binding technique, prenalterol (3.8 mg/kg/hr) infused intraperitoneally through osmotic minipumps, penetrated the brain and significantly inhibited the binding of the beta adrenoceptor antagonist, [125I]iodopindolol (125I-IPIN), to cortical beta adrenoceptors. Infusion of prenalterol (3.8 mg/kg/hr) for 7 days resulted in a small (20%), but significant, reduction in the ability of isoproterenol to stimulate maximally the accumulation of cyclic AMP in slices of cerebral cortex. No alteration in the Bmax or KD of the binding of [125I]iodopindolol was observed in homogenates of cortex obtained from prenalterol-treated rats. Furthermore, no change was observed in the binding of the hydrophilic ligand [3H]CGP-12177 in homogenates of cortex. In this study, then, prenalterol exhibited properties in vitro of a beta adrenoceptor antagonist, but did cause modest desensitization of beta adrenoceptor responsiveness when administered continuously in vivo.

Effects of methylphenidate on rat endurance performance and neuromuscular transmission in vitro.

The studies were designed to evaluate the effects of methylphenidate on endurance performance in vivo and on neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Methylphenidate produced a biphasic effect on treadmill endurance performance, increasing running times by 41-61% at 2.5-5 mg/kg, while reducing running times by 35% at 20 mg/kg. A biphasic effect on nerve-stimulated muscle concentrations was also observed, with twitch tension increased by up to 49-106% at low concentrations (0.1-0.3 mM) and blocked at high concentrations (0.6-1.0 mM). Tissues obtained from rats pretreated with alpha-methyl-p-tyrosine or reserpine exhibited no change in twitch height. Methylphenidate failed to protect against irreversible blocking of the twitch by alpha-bungarotoxin and did not modify the resting membrane potential, miniature endplate potential (MEPP) frequency or nerve-stimulated acetylcholine release. High concentrations reduced the amplitudes of the MEPP and endplate potential. Whereas methylphenidate and amphetamine both produced biphasic effects on skeletal muscle contractions in vitro, they act by different neuropharmacological mechanisms. Unlike amphetamine, the biphasic effects of methylphenidate are produced by mechanisms that are independent of cholinergic or adrenergic interactions and may involve direct effects on the muscle.

Age-related change in alpha-adrenergic responsiveness of the urinary bladder of the rat is regionally specific.

The effects of age on the responsiveness of the body of the urinary bladder and base of the bladder to alpha-adrenergic agonists were studied. Regions of the bladder were isolated from Fischer 344 rats, ages 7, 16, and 27 months. Maximum isotonic contractions elicited by potassium chloride (KCl) in both regions of the bladder were unaffected by age. In the bladder body there was an age-related increase in the maximum contraction elicited by phenylephrine, norepinephrine and clonidine. No such alteration in responsiveness was observed in the base of the bladder with age. The ED50 values of all three agonists were unchanged with age in both regions of the bladder. The pA2 values of prazosin and yohimbine were approximately 8.5 and 6.0, respectively, in the body of the bladder, and these values were not altered by age. Thus, it is concluded that an age-related increase occurs in the responsiveness of the body of the bladder to alpha-adrenergic activation and that these changes are mediated by alpha 1-adrenoceptors.

Alpha2C-adrenoceptors mediate inhibition of forskolin-stimulated cAMP production in rat striatum.

The potential role of alpha2-adrenoceptors in modulating the activity of adenylyl cyclase in the rat striatum was examined. The selective alpha2-adrenoceptor agonist, UK14,304, produced a concentration-dependent inhibition of forskolin-stimulated accumulation of cAMP in striatal slices. The effect of UK14,304 was reversed by pre-incubation of striatal slices with the selective alpha2-adrenoceptor antagonist, RX821002. To determine whether alpha2C-adrenoceptors contribute to the alpha2-adrenoceptor-induced inhibition of forskolin-stimulated cAMP accumulation, an antisense oligodeoxynucleotide directed against alpha2C-adrenoceptor mRNA (alpha(2C)AS) or a random sequence (RS) was infused directly into the striatum. The ability of alpha(2C)AS to reduce the expression of alpha2C-adrenoceptors has been previously demonstrated. Alpha2C(AS) infusions did not reduce the ability of UK14,304 to inhibit forskolin-stimulated cAMP accumulation. Instead, alpha(2C)AS significantly enhanced forskolin-stimulated cAMP accumulation on the infusion side compared to the contralateral striatum. In contrast to the effects of alpha(2C)AS, infusions of RS had no effects on forskolin-stimulated cAMP accumulation or on the ability of UK14,304 to inhibit this effect. Incubation of striatal slices from untreated rats with RX821002 could mimic the ability of alpha(2C)AS infusion to enhance forskolin-stimulated cAMP accumulation, and did so in a concentration-dependent manner. Alpha2-adrenoceptors are negatively coupled to adenylyl cyclase in the rat striatum and alpha2C-adrenoceptors appear to be under tonic activation by an endogenous ligand in striatal slices.

Reduced expression of alpha2C-adrenoceptors in rat striatum following antisense oligodeoxynucleotide infusion.

The predominate subtypes of alpha2-adrenoceptors in the brain are alpha2A and alpha2C. The lack of selective ligands for these receptors hampers their functional characterization. We exploited an antisense strategy as an alternative pharmacological tool to study alpha2C-adrenoceptors. In rat striatum (caudate-putamen), alpha2-adrenoceptors were characterized using the subtype-non-selective antagonist [3H]2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline ([3H]RX821002). Specific [3H]RX821002 binding was saturable and to a single class of high-affinity sites. Curves for the inhibition of [3H]RX821002 binding by the alpha2C-selective compound, prazosin, were fit best by a model assuming binding to two sites, presumably reflecting binding to alpha2A- and alpha2C-adrenoceptors. A 15-mer phosphorothioate oligodeoxynucleotide (alpha2C AS) complementary to the alpha2C-adrenoceptor mRNA, or a random sequence (RS) was administered to rats continuously for 4.5 days directly into the striatum. Compared to RS infusions, alpha2C AS infusions induced a 35% reduction in the Bmax of [3H]RX821002 in striatal homogenates (P < 0.05). Curves for the inhibition of [3H]RX821002 binding by prazosin were fit best by a model assuming a single interaction in alpha2C AS-infused rats and to a model assuming two sites in RS-infused rats. These results are consistent with the conjecture that both alpha2A- and alpha2C-adrenoceptors occur in the rat striatum and also demonstrate the feasibility of an antisense approach to examine the functional role of subtypes of alpha2C-adrenoceptors in the brain.

On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns.

RATIONALE: Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that determine relative effectiveness of drugs as reinforcers will enhance our understanding of drug abuse. OBJECTIVES: The hypothesis of the present study was that differences among dopamine transporter (DAT) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as DA uptake inhibitors. Accordingly, self-administration of a group of local anesthetics that are DAT ligands was compared to their effects as DA uptake blockers in vitro in brain tissue. METHODS: Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v. under a progressive-ratio schedule. The same compounds were compared in standard in vitro DA uptake assays using monkey caudate tissue. RESULTS: The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting DA uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine. At maximum, these compounds were equally effective in blocking DA uptake. Lidocaine did not inhibit DA uptake. CONCLUSIONS: The potency of local anesthetics as positive reinforcers is likely related to their potency as DA uptake inhibitors. Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as DA uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics.

Role of the dopamine transporter and the sodium channel in the cocaine-like discriminative stimulus effects of local anesthetics in rats.

RATIONALE: Local anesthetics bind to the dopamine transporter (DAT), inhibit dopamine (DA) uptake and have been reported to have cocaine-like discriminative stimulus effects. The hypothesis of the present study was that affinity at the DAT and potency as a DA uptake blocker determines potency as a cocaine-like discriminative stimulus among local anesthetics, and maximum DA uptake inhibition determines maximum cocaine-like discriminative stimulus effects. OBJECTIVES: Cocaine-like discriminative potency was compared to DAT affinity and DA uptake inhibition potency, and maximum cocaine-like discriminative stimulus effects were compared to maximum DA uptake inhibition for procaine, chloroprocaine, dimethocaine, tetracaine and lidocaine. METHODS: Discriminative stimulus effects were determined in two groups of rats using 10 mg/kg and 3.0 mg/kg cocaine training doses. DAT affinity and DA uptake inhibition effects were determined in vitro in rat caudate nucleus tissue. Additionally, sodium channel affinity was determined in rat frontal cortex tissue. RESULTS: In the 10 mg/kg group, none of the local anesthetics fully substituted for cocaine and all decreased response rate. Rate decreasing potencies were positively correlated with sodium channel affinities. In the low training dose group, all the local anesthetics except tetracaine substituted fully for cocaine. Discriminative potencies were positively correlated with sodium channel affinities. Maximum DA uptake inhibition did not adequately predict maximum discriminative stimulus effects. CONCLUSIONS: Cocaine-like discriminative stimulus effects of local anesthetics were more prominent at a low than at a high training dose of cocaine. Sodium channels seem to have a direct influence on discriminative effects at low cocaine doses, whereas they have an indirect influence on discriminative effects at high cocaine doses by decreasing response rates.

Pathophysiology of the locus coeruleus in suicide.

Clinical and basic research findings implicate a role for brain norepinephrine in the pathophysiology of psychiatric disorders that can lead to suicide. However, the precise biological abnormality of neurons that produce norepinephrine in the brain in these disorders has not been elucidated. We have studied the biochemistry of the locus coeruleus (LC), the principal source of brain norepinephrine, from suicide victims and from age-matched, natural or accidental death control subjects. Levels of tyrosine hydroxylase (rate-limiting enzyme in norepinephrine biosynthesis) and amounts of binding to a2 adrenoceptors (norepinephrine receptors) are elevated in the LC of suicide victims as compared to control subjects. These biological abnormalities in the LC from suicide victims are very similar to biochemical changes observed in the rat LC following repeated exposure to environmental stimuli that activate the LC or to treatment with pharmacological agents that deplete brain norepinephrine. It is hypothesized that persons who commit suicide have experienced chronic activation of the LC, resulting in depletion of synaptic norepinephrine and compensatory changes in concentrations of noradrenergic proteins.

Function of mature coronary collateral vessels and cardiac performance in the exercising dog.

Formation of extensive collateral vessels after chronic constriction of a coronary artery in dogs can provide for similar increases in blood flow to native and collateralized regions of myocardium during exertion. Previous investigations have not compared myocardial blood flow and cardiac functional responses during exercise in constricted and nonconstricted (sham) animals. Thus we evaluated left ventricular performance and myocardial blood flow at rest and during mild, moderate, and severe exertion in sham-operated dogs and in dogs 2-3 mo after placement of an Ameroid occluder around the proximal left circumflex artery. Changes in double product, maximal left ventricular dP/dt, and pressure-work index were similar in both groups for each level of exertion. Despite similar increases in estimated myocardial O2 demand and similar diastolic perfusion pressures, average transmural myocardial blood flow increased less in the constrictor animals, particularly during severe exercise (2.74 +/- 0.22 vs. 1.45 +/- 0.29 ml X min-1 X g-1). The smaller increases in blood flow occurred equally in native and collateralized regions as well as in the papillary muscles and boundary areas between the native and collateralized regions. The differences in flow in the native and collateralized regions were uniform across the wall of the myocardium. We also observed smaller increases in stroke volume and cardiac output in the constrictor group, disparities which increased with increasing exertion (stroke volume, severe exercise = 0.92 +/- 0.13 vs. 0.53 +/- 0.09 ml/kg). We postulate that myocardial active hyperemia is limited either because the coronary vessels remaining after chronic circumflex occlusion cannot dilate sufficiently or that there is inappropriate active vasoconstriction during severe exertion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of PEEP on discharge of pulmonary C-fibers in dogs.

Although positive end-expiratory pressure (PEEP) is believed to depress cardiac output and arterial pressure by compressing the vena cava and the heart, it is unclear whether PEEP also depresses these variables by a reflex arising from an inflation-induced stimulation of pulmonary C-fibers. We therefore recorded the impulse activity of 17 pulmonary C-fibers in barbiturate-anesthetized dogs with closed chests, while we placed the expiratory outlet of a ventilator under 5-30 cmH2O. Increasing PEEP in a ramp-like manner stimulated 12 of the 17 pulmonary C-fibers, with activity increasing from 0.0 +/- 0.1 to 0.9 +/- 0.2 imp/s when end-expiratory pressure equaled 15 cmH2O. When PEEP was increased in a stepwise manner to 15-20 cmH2O and maintained at this pressure for 15 min, pulmonary C-fibers increased their firing rates, but the effect was small averaging 0.2-0.3 imp/s after the 1st min of this maneuver. We conclude that pulmonary C-fibers are unlikely to be responsible for causing much of the decreases in cardiac output and arterial pressure evoked by sustained periods of PEEP in both patients and laboratory animals. These C-fibers, however, are likely to be responsible for causing the reflex decreases in these variables evoked by sudden application of PEEP.

Exercise-induced functional desensitization of canine cardiac beta-adrenergic receptors.

To test the hypothesis that the high levels of endogenous catecholamines associated with strenuous exercise produce functional desensitization of cardiac beta-adrenergic receptors, we measured the bolus chronotropic dose of isoproterenol necessary to produce a 25-beats/min increase in heart rate (CD25) in the resting state and after the return of heart rate to resting levels after 60 min of treadmill running in 13 normal dogs. Immediately after exercise, 12 of 13 dogs were less sensitive to the chronotropic effects of beta-adrenergic receptor stimulation: mean CD25 increased from 1.16 +/- 0.17 to 3.50 +/- 0.98 micrograms (P less than 0.02). A similar reduction in isoproterenol sensitivity was evident regardless of whether testing was performed in the presence or absence of vagal blockade with atropine. By 3 h after exercise, CD25 had returned to the preexercise level, with no further change noted 24 h after exercise. There was no change in the CD25 when measured serially in three unexercised dogs. We conclude that a single bout of dynamic exercise is sufficient to produce a significantly decreased chronotropic responsiveness to isoproterenol. This phenomenon may represent an acute but transient desensitization of cardiac beta-adrenergic receptors.

Dynamic exercise training in foxhounds. II. Analysis of skeletal muscle.

The purpose of this study was to determine whether 8-12 wk of endurance training produces biochemical and histochemical adaptations in skeletal muscle in foxhounds. Analyses were performed on samples removed from gastrocnemius, triceps, and semitendinosus muscles of foxhounds before and after a treadmill running program. Biochemical analysis showed that training did not alter the activities of phosphofructokinase, beta-hydroxyacyl-CoA dehydrogenase, succinate dehydrogenase, or total phosphorylase. Histochemical analysis of myofibrillar actomyosin ATPase demonstrated three distinct classes of type II fibers and one type I fiber in the semitendinosus and triceps muscles and two type II and two type I fibers in the gastrocnemius muscle. Fiber type distribution and oxidative and glycolytic potentials, as indicated by nicotinamide adenine dinucleotide tetrazolium reductase or alpha-glycerophosphate dehydrogenase staining intensity, were unaltered by training. Similarly, capillary density, capillary-to-fiber ratios, and capillary area-to-fiber area ratios did not change with training. Thus, unlike humans and other mammals (i.e., rat), these foxhounds did not manifest biochemical or histochemical adaptations in skeletal muscle as the result of endurance training. This is consistent with the results of the study in which endurance training produced a 27% increase in maximal cardiac output and a 4% increase in maximal arteriovenous O2 extraction in foxhounds.